Acute lung injury (ALI) is a devastating syndrome marked by alveolar edema, severe hypoxemia and unacceptably high mortality. Decreased pulmonary epithelial cell barrier function is central to the pathophysiology of acute lung injury, but our current understanding of the mechanisms leading to increased epithelial permeability is limited. Recently, activation of the human epidermal growth factor receptor 2 (HER2) by ADAM17-mediated shedding of the ligand neuregulin-1 (NRG-1) was demonstrated to increase pulmonary epithelial permeability and participate in ALI pathogenesis. The purpose of the current application is to determine the mechanisms of ADAM17 activation and define a requirement for ADAM17-mediated NRG-1 shedding and HER2 activation in ALI. Using a combination of in vitro and in vivo studies, we propose to test the overall hypothesis that IL-1 induces a signaling cascade resulting in ADAM17 activation and NRG-1 shedding leading to HER2 activation, increased para-cellular epithelial permeability and ALI. The specific aims are: Hypothesis 1: Tyrosine phosphorylation of ADAM17 is required for ADAM17 activation and NRG-1 shedding in pulmonary epithelium. Specific Aim 1: Determine the role of tyrosine phosphorylation in ADAM17 activation and NRG-1 shedding in pulmonary epithelial cells. 1.1: Define the role of ADAM17 tyrosine phosphorylation in ADAM17-mediated NRG-1 shedding. 1.2: Define the role of Src family kinases in ADAM17 tyrosine phosphorylation and NRG-1 shedding. Hypothesis 2: ADAM17-mediated shedding of NRG-1 from pulmonary epithelium results in HER2 activation and is required for ALI in vivo. Specific Aim 2: Define ADAM17-mediated NRG-1 shedding and HER2 activation from pulmonary epithelial cells as a requirement for ALI in vivo. 2.1: Determine the effect of ADAM17 down-regulation on ALI in vivo. 2.2: Determine the effect of NRG-1 down-regulation on ALI in vivo. 2.3: Determine the role of HER2 blockade on ALI in vivo. PUBLIC HEALTH RELEVANCE: Acute lung injury (ALI) is a devastating illness marked by increases in permeability of the lung resulting in flooding of the lung with edema fluid. While there have been some recent advances, treatment is largely supportive and unsuccessful. The purpose of this application is to study how ADAM17 sheds the protein neuregulin-1 from the surface of lung cells, leading to neuregulin-1 binding to the receptor HER2 and subsequent increases in permeability of the lung and ALI.